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3.
Heart Lung ; 48(1): 22-27, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30172414

RESUMO

INTRODUCTION: Digitalis has been used for over 200 years to treat patients with heart failure, and evidence supports its use to improve clinical symptoms and quality of life, but not survival. The objective of this retrospective study was to evaluate the effects of digitalis on readmission and mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were receiving current guideline recommended medical therapy. METHODS: We reviewed medical record data from a retrospective cohort study of 1047 patients admitted to the hospital from 2005 to 2014 with decompensated HFrEF. 244 received digitalis, at some point during patient trajectory, and 803 never received digitalis. The primary outcomes of interest were the length of stay in hospital, readmission rates after discharge at 1, 6, 12, and 24 months and the overall mortality rate, at the same time points. RESULTS: We studied the effects of digitalis after adjusting for age, sex, race, potentially confounding comorbidities, and prescription medications. Digitalis treatment is associated with decreases in EF in patients with HFrEF (OR = -2.83, P < 0.001) and was associated with an increased readmission rate for any reason after discharge from the hospital at 6, 12, and 24 months, 53%, 34%, and 35%, respectively. No statistically significant difference was found between patients who received digitalis and those who did not (referent group) for the length of hospital stay and overall mortality rate. CONCLUSION: Digitalis use is associated with increased re-admission rates for any reason following discharge from the hospital at 6, 12, and 24 months.


Assuntos
Digoxina/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Readmissão do Paciente/tendências , Qualidade de Vida , Volume Sistólico/fisiologia , Idoso , Cardiotônicos/farmacocinética , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Humanos , Alta do Paciente/tendências , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
4.
Clin Biochem ; 63: 102-105, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30316751

RESUMO

BACKGROUND: Due to the narrow therapeutic range of digoxin, determining serum/plasma digoxin concentrations is critical for assessing patients with congestive heart failure, atrial fibrillation, and certain types of arrhythmias. However, digoxin quantification by competitive immunoassays is susceptible to interferences that may alter the accuracy of its measurement in patient plasma. This study aimed to characterize the extent of bilirubin interference in three commonly used digoxin immunoassays. METHODS: Digoxin concentrations were compared using the Beckman Coulter® Unicel DxI 800, the Vitros® 4600, and the Roche Cobas® 8000 in neat or digoxin-spiked icteric and non-icetric plasma samples. A mixing study was performed to demonstrate how digoxin quantification is affected by bilirubin. An equation was derived that predicts the response of the DxI 800, given known bilirubin and digoxin concentrations. RESULTS: The DxI reported detectable concentrations of digoxin in high bilirubin samples with no added digoxin, while the Vitros® 4600 and Cobas® 8000 gave virtually undetectable results. Spiking digoxin into samples with elevated bilirubin concentrations resulted in a higher percent recovery for the DxI 800 when compared to the other two platforms. The mixing study also revealed an increase in the percent recovery in the DxI 800, while the Vitros® 4600 and Cobas® 8000 were comparable to the expected concentration of digoxin. CONCLUSIONS: The DxI 800 is most prone to interference by bilirubin, while the Vitros® 4600 and Cobas® 8000 are relatively unaffected. Icteric samples should be interpreted with caution if digoxin quantification is needed, especially on the DxI 800 assay.


Assuntos
Arritmias Cardíacas/sangue , Bilirrubina/sangue , Digoxina/farmacocinética , Monitoramento de Medicamentos/métodos , Insuficiência Cardíaca/sangue , Arritmias Cardíacas/tratamento farmacológico , Monitoramento de Medicamentos/instrumentação , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Imunoensaio/métodos
5.
Curr Drug Metab ; 20(2): 124-129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30280663

RESUMO

BACKGROUND: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs. OBJECTIVE: Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies. CONCLUSION: Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dabigatrana/farmacocinética , Digoxina/farmacocinética , Propanolaminas/farmacocinética , Terfenadina/análogos & derivados , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Humanos , Terfenadina/farmacocinética
6.
Clin Toxicol (Phila) ; 57(2): 117-124, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30306803

RESUMO

CONTEXT: Recommended doses of digoxin-specific antibody fragments (digoxin-Fab) for treatment of acute digoxin poisoning are pharmacokinetically unsubstantiated and theoretically excessive. Physiologically based pharmacokinetic (PBPK) modelling creates clinical simulations which are closely related to physiological and pharmacokinetic behaviour. This paper details the formulation of a PBPK model of digoxin and explores its use as a simulation tool for acute digoxin toxicity and its management. MATERIALS AND METHODS: A PBPK model of digoxin was constructed and validated for acute digoxin poisoning management by comparing simulations with observed individual acute overdose patients. These simulations were compared with standard two-compartment PK model simulations. RESULTS: PBPK model simulations showed good agreement with post-absorption plasma concentrations of digoxin measured in 6 acute overdose patients. PBPK predictions were accurate to 1.5-fold or less of observed clinical values, proving to be more accurate than two-compartment simulations of the same patients which produced up to a 4.9-fold change. CONCLUSIONS: Compared to conventional two-compartment modelling, PBPK modelling is superior in generating realistic simulations of acute digoxin toxicity and the response to digoxin-Fab. Simulation capacity provides realistic, continuous data which has the potential to substantiate alternative, less expensive, and safer digoxin-Fab dosing strategies for the treatment of acute digoxin toxicity.


Assuntos
Digoxina/toxicidade , Fragmentos de Imunoglobulinas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Digoxina/sangue , Digoxina/imunologia , Digoxina/farmacocinética , Overdose de Drogas/sangue , Overdose de Drogas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos
7.
Am J Ther ; 26(1): e54-e65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-26808357

RESUMO

Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.


Assuntos
Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Modelos Biológicos , Área Sob a Curva , Cardiotônicos/administração & dosagem , Digoxina/administração & dosagem , Esquema de Medicação , Interações de Medicamentos , Monitoramento de Medicamentos , Voluntários Saudáveis , Humanos , Modelos Lineares , Masculino , Estudos Prospectivos
8.
Drug Metab Dispos ; 47(2): 71-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30478157

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (-/-) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Digoxina/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Encéfalo/metabolismo , Sistemas CRISPR-Cas/genética , Citocromo P-450 CYP3A/análise , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Digoxina/administração & dosagem , Feminino , Técnicas de Inativação de Genes/métodos , Intestino Delgado/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Modelos Animais , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
9.
Int J Clin Pharmacol Ther ; 57(2): 101-109, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30309450

RESUMO

OBJECTIVE: Digoxin is a glycosidic, cardiotonic plant extract with a narrow therapeutic window. The purpose of the study was to investigate the effects of purple grape juice on the pharmacokinetics of digoxin in rats. MATERIALS AND METHODS: A randomized, controlled, single- and multiple-dose study was conducted to evaluate the pharmacokinetic profiles of orally and intravenously administered digoxin. The plasma concentration of digoxin was determined by radioimmunoassay using a gamma counter, and a Caco-2 cell transport model was used to investigate the potential mechanism by which purple grape juice affects the pharmacokinetics of digoxin. RESULTS: The results show that multiple-dose purple grape juice caused a remarkable increase in the AUC, Cmax, and Ka of orally administered digoxin (p < 0.05); only a single dose increased the digoxin AUC0-∞ by 72.80% (p < 0.05). Other parameters were not significantly affected. The study of intravenously administered digoxin found no significant difference in the pharmacokinetic characteristics of the two dosing groups (p > 0.05). The Caco-2 transwell experiments indicated that both the pure purple grape juice and its ethyl acetate extract significantly inhibited digoxin basolateral-to-apical (B→A) transport at concentrations of 10%, 30%, and 50% with dose dependency. These results confirmed that the improvement in bioavailability of digoxin resulted from the inhibition of P-gp by purple grape juice at the level of the gastrointestinal wall. CONCLUSION: Purple grape juice can increase the bioavailability of orally administered digoxin, especially with multiple doses. This information suggests that co-administration of oral digoxin and purple grape juice may require a dose adjustment.
.


Assuntos
Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Interações Alimento-Droga , Sucos de Frutas e Vegetais , Vitis , Animais , Área Sob a Curva , Células CACO-2 , Humanos , Distribuição Aleatória , Ratos
10.
Zhongguo Zhong Yao Za Zhi ; 43(20): 4132-4137, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30486542

RESUMO

Shuxiong prescription (Notoginseng Radix et Rhizoma, Chuanxiong Rhizome and Carthami Flos) has the function of activating blood circulation to dissipate blood stasis, activating meridians to stop pain. This paper was mainly aimed to discuss the transport characteristics of Shuxiong prescription across Caco-2 cell monolayer. Safe concentration range of Shuxiong prescription against Caco-2 cell monolayer model was determined by MTT assay. The mechanism of Shuxiong prescription bidirectional transport was investigated by Caco-2 cell monolayer model. The apparent permeability coefficient Papp of digoxin was determined by high performance liquid chromatography (HPLC). The test results showed that the Papp of extract from Notoginseng Radix et Rhizoma, Chuanxiong Rhizome, Carthami Flos, Chuanxiong Rhizome+Carthami Flos and Shuxiong prescription transport from apical (AP) side to basolateral (BL) side was (3.12±0.73)×10⁻6, (2.58±0.41)×10⁻6, (4.97±0.64)×10⁻6, (4.63±0.57)×10⁻6, (5.79±0.68)×10⁻6 cm·s⁻¹, respectively, indicating that the transport of digoxin across Caco-2 cell monolayer model was active absorption, and the P-gp protein took part in the process. Chuanxiong Rhizome could significantly decrease the transport of digoxin from BL→AP(P<0.01) and increase its transport from AP→BL(P<0.05) significantiy. After the addition of Shuxiong prescription, the transport of digoxin from BL→AP was significantly inhibited(P<0.01). The results suggested that the extract of safflower had no effect on P-gp transport, nor on the independence diffusion of digoxin. The transport of digoxin could be degraded by the extract of Chuanxiong Rhizome and the extract of Shuxiong prescription from BL→AP(P<0.01), significantly; pseudo-ginseng had no effect on the independence diffusion of digoxin; the extract of safflower+Chuanxiong Rhizome had the same experimental result as Chuanxiong Rhizome extract.


Assuntos
Digoxina/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Transporte Biológico , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Humanos
11.
Pharm Res ; 36(1): 1, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30402714

RESUMO

PURPOSE: A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition. METHODS: Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined. RESULTS: Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant.


Assuntos
Bupropiona/farmacocinética , Digoxina/farmacocinética , Administração Oral , Animais , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Humanos , Macaca fascicularis , Metaboloma , Metabolômica , Distribuição Tecidual
12.
J Pharmacol Toxicol Methods ; 94(Pt 2): 64-72, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30244071

RESUMO

INTRODUCTION: Ouabain and digoxin are classical inhibitors of the Na+,K+-ATPase. In addition to their conventional uses as therapeutic agents or experimental tools there is renewed interest due to evidence suggesting they could be endogenous hormones. Somewhat surprisingly, different publications show large discrepancies in potency for inhibiting Na+,K+-ATPase activity (IC50), particularly for the slow binding inhibitors, ouabain and digoxin. METHODS: Using purified pig kidney Na+,K+-ATPase (α1ß1FXYD2) and purified detergent-soluble recombinant human Na+,K+-ATPase (α1ß1FXYD1) we have re-evaluated binding and inhibition kinetics and effects of K+ concentration for ouabain, digoxin, ouabagenin and digoxigenin. RESULTS: We demonstrate unequivocally that for slow binding inhibitors, ouabain and digoxin, long incubation times (≥60 min at 37 °C) are required to avoid under-estimation of potency and correctly determine inhibition (IC50 around 100-200 nM at 5 mM K+) contrary to what occurs when pre-incubation of the drugs without ATP is followed by a short incubation time. By contrast, for the rapidly bound inhibitors, ouabagenin and digoxigenin, short incubation times suffice (<10 min). The strong reduction of inhibitory potency observed at high un-physiological K+ concentrations (≥5 mM) also explained the low potency reported by some authors. DISCUSSION: The data resolve discrepancies in the literature attributable to sub-optimal assay conditions. Similar IC50 values are obtained for pig kidney and recombinant human Na+,K+-ATPase, showing that inhibitory potencies are not determined by the species difference (pig versus human) or environment (membrane-bound versus detergent-soluble) of the Na+,K+-ATPase. The present methodological considerations are especially relevant for drug development of slow binding inhibitors.


Assuntos
Glicosídeos Cardíacos/farmacologia , Glicosídeos Cardíacos/farmacocinética , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Digoxigenina/farmacocinética , Digoxina/farmacocinética , Humanos , Rim/enzimologia , Ouabaína/análogos & derivados , Ouabaína/farmacocinética , Ligação Proteica , Relação Estrutura-Atividade , Suínos
14.
Int J Pharm ; 551(1-2): 148-157, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30218825

RESUMO

The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin was evaluated at two concentration levels: 1.0 µg/ml (with and without sodium azide 65.0 µg/ml) and 6.0 µg/ml. These concentrations correspond to the ratio of the highest dose strength (0.25 mg) and the highest single dose administered (1.5 mg) and the 250 ml of water. In situ closed loop perfusion studies in rats were performed in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of P-gp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not saturated and then it could be inhibited by other drugs, excipients or food components leading to the already reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of view these interactions.


Assuntos
Cardiotônicos/classificação , Cardiotônicos/farmacocinética , Digoxina/classificação , Digoxina/farmacocinética , Absorção Intestinal , Modelos Biológicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Biofarmácia , Intestino Delgado/metabolismo , Masculino , Perfusão , Ratos Wistar
15.
Drug Des Devel Ther ; 12: 2139-2147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022812

RESUMO

Background: Previous in vitro studies have reported the inhibitory effect of green tea on p-glycoprotein (p-gp) encoded by ABCB1. This study aimed to investigate the effect of green tea on the pharmacokinetics of digoxin, a typical probe drug of p-gp. Methods: Sixteen healthy volunteers participated in this study. At Day 1, 0.5 mg of digoxin was administered via oral route. After a 14-day washout period, 630 mg of green tea catechins (GTC) was administered via oral route, followed by 0.5 mg of digoxin 1 hour later. From Day 16 through Day 28, 630 mg of GTC was administered alone. At Day 29, 630 mg of GTC and 0.5 mg of digoxin were administered in the same way as Day 15. Blood samples for the pharmacokinetic assessments of digoxin were collected up to 8 hours after each dose. Pharmacokinetic parameters were estimated by noncompartmental analysis. Area under the curve (AUC) and peak plasma concentration (Cmax) were compared using mixed effect model between digoxin alone and digoxin with GTC. ABCB1 was genotyped to determine whether its polymorphism affects digoxin-GTC interaction. Results: Fifteen subjects completed the study. Compared to digoxin alone, the concomitant administration of digoxin and GTC significantly reduced the systemic exposure of digoxin: geometric mean ratios (GMR) and 90% confidence intervals (CI) of area under the concentration-time curve from time 0 to the last measurable time (AUClast) and Cmax were 0.69 (0.62-0.75) and 0.72 (0.61-0.85), respectively. The concomitant administration of digoxin and GTC following pretreatment of GTC (Day 29) similarly reduced the AUClast (GMR [90% CI]: 0.67 [0.61-0.74]) and Cmax (GMR [90% CI]: 0.74 [0.63-0.87]). In the comparison of the percentage changes from Day 1 (digoxin single administration) of AUClast between genotypes, C1236T variant type showed a significant difference to wild-type on Day 15 (concomitant administration of digoxin and GTC) (P=0.005). Conclusion: This study demonstrates that the coadministration of GTC reduces the systemic exposure of digoxin regardless of pretreatment of GTC.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Catequina/farmacocinética , Digoxina/farmacocinética , Extratos Vegetais/farmacocinética , Chá/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Adulto , Catequina/administração & dosagem , Catequina/química , Digoxina/administração & dosagem , Digoxina/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , República da Coreia , Adulto Jovem
16.
Eur J Pharm Sci ; 122: 77-84, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29933077

RESUMO

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfbret/ret mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (Kp,brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (fu,brain) and plasma (fu,plasma). This enabled estimation of unbound drug partitioning coefficients (Kp,uu,brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfbret/ret mice as reflected in Kp,brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar Kp,uu,brain values in Pdgfbret/ret and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.


Assuntos
Encéfalo/metabolismo , Pericitos/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Diazepam/farmacocinética , Digoxina/farmacocinética , Feminino , Levofloxacino/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Oxicodona/farmacocinética , Palmitato de Paliperidona/farmacocinética , Ligação Proteica
17.
Br J Clin Pharmacol ; 84(9): 1941-1949, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29665130

RESUMO

AIMS: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin. METHODS: In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug. RESULTS: Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI. CONCLUSIONS: Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.


Assuntos
Desenvolvimento de Medicamentos/métodos , Interações de Medicamentos , Proteínas de Membrana Transportadoras/metabolismo , Adulto , Área Sob a Curva , Estudos Cross-Over , Digoxina/administração & dosagem , Digoxina/metabolismo , Digoxina/farmacocinética , Relação Dose-Resposta a Droga , Furosemida/administração & dosagem , Furosemida/metabolismo , Furosemida/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Metformina/administração & dosagem , Metformina/metabolismo , Metformina/farmacocinética , Pessoa de Meia-Idade , Eliminação Renal , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Adulto Jovem
19.
J Am Coll Cardiol ; 71(10): 1063-1074, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29519345

RESUMO

BACKGROUND: Digoxin is widely used in patients with atrial fibrillation (AF). OBJECTIVES: The goal of this paper was to explore whether digoxin use was independently associated with increased mortality in patients with AF and if the association was modified by heart failure and/or serum digoxin concentration. METHODS: The association between digoxin use and mortality was assessed in 17,897 patients by using a propensity score-adjusted analysis and in new digoxin users during the trial versus propensity score-matched control participants. The authors investigated the independent association between serum digoxin concentration and mortality after multivariable adjustment. RESULTS: At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score-matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users. CONCLUSIONS: In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations ≥1.2 ng/ml. Initiating digoxin was independently associated with higher mortality in patients with AF, regardless of heart failure.


Assuntos
Fibrilação Atrial , Causas de Morte , Morte Súbita , Digoxina , Insuficiência Cardíaca , Idoso , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Antiarrítmicos/sangue , Antiarrítmicos/farmacocinética , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Correlação de Dados , Morte Súbita/epidemiologia , Morte Súbita/etiologia , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Digoxina/sangue , Digoxina/farmacocinética , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco
20.
J Clin Pharm Ther ; 43(3): 377-384, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29365353

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Digoxin is commonly prescribed for heart failure patients with reduced ejection fraction (HFrEF) and patients with atrial fibrillation (AF). Due to digoxin's narrow therapeutic range, monitoring the serum digoxin concentration (SDC) is important. However, the SDC measurement is not widely available. Equations using clinical parameters can be employed to estimate the SDC but have never been studied in the Thai population. Therefore, we conducted this study to evaluate the correlation between the measured SDC and predicted digoxin level using 2 commonly used equations: the Konishi equation and the Koup and Jusko equation. METHODS: This report describes prospective, cross-sectional study conducted at Chiang Mai University. One hundred and fourteen patients were recruited in the study. All of the patients were diagnosed as having HFrEF, AF or both and had been receiving digoxin for at least 4 weeks. The SDC of each patient was measured at steady state and assigned to one of 3 groups according to the classifications of the Digitalis Investigation Group (DIG) trial: in the therapeutic range, over the therapeutic range and in the suboptimal range. RESULTS AND DISCUSSION: There were significant correlations between the measured and predicted SDCs using both the Konishi equation and the Koup and Jusko equation, which had correlation coefficients (R) of 0.69 and 0.31 (P < .05 for both), respectively. The percentages of patients with measured SDCs in the therapeutic range, over the therapeutic range and in the suboptimal range were 27.2%, 9.6% and 63.2%, respectively. The sensitivity and specificity of the Konishi equation in predicting SDCs in the over the therapeutic range were 72.73% (95% Confidence interval (CI): 39.03%-93.98%) and 80.58% (95% CI: 71.62%-87.72%), respectively. Of the 5 patients (4.4%) who were rehospitalized, 2 patients (0.01%) were readmitted due to acute decompensated heart failure (ADHF). One of the patients had an SDC that was over the therapeutic range. None of the readmitted patients had ventricular arrhythmia. WHAT IS NEW AND CONCLUSIONS: The Konishi equation yielded better predictions of the SDC, especially in the subgroup of HFrEF patients. Furthermore, the prediction of SDCs in the over the therapeutic range using this equation was superior to that of the Koup and Jusko equation. With further validation in a larger population, this equation should facilitate the detection of patients who are over the therapeutic range in clinical practice.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Modelos Teóricos , Idoso , Cardiotônicos/administração & dosagem , Estudos Transversais , Digoxina/administração & dosagem , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Estudos Prospectivos , Sensibilidade e Especificidade , Volume Sistólico , Tailândia
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